Manchester City manager Mark Hughes saw his side finish top of their UEFA Cup group - despite being second best in Spain.
FC Twente's defeat by Paris St Germain means City will now face a third-placed team from one of the other groups in the draw tomorrow.
With qualification already assured Hughes gave a number of fringe players a run-out and they did themselves no favours.
The result brought to an end City's good away record in Europe which had seen them win six of their last seven matches on the road going into this game.
With only four players retained from the weekend - Robinho, Elano, Micah Richards and Pablo Zabaleta - they looked like a team of strangers.
City found themselves two goals down by half-time and could hardly complain given the paucity of their game.
Robinho did not appear for the second half with a vital Barclays Premier League game against West Brom to come on Sunday at the Hawthorns.
The tone was set as a early as the eighth minute when a poor clearance from goalkeeper Kasper Schmeichel almost proved costly.
The ball landed at the feet of Mohamed Tchite but his effort finished the wrong side of the post.
Play switched down the other end and Ivan Marcano was hauled back for a challenge on young City striker Ched Evans.
However Javier Garrido failed to test the goalkeeper, his free-kick going high over the bar.
Santander responded in the 14th minute and Marcano picked out Juan Valera but Schmeichel saved his header with a degree of comfort.
The home side took the lead in the 18th minute when Schmeichel failed to deal with a routine cross from Oscar Serrano.
Schmeichel only succeeded in pushing the ball into the path of Jonathan Pereira, who tapped the ball home.
Pereira rattled in a shot from 25 yards but the goalkeeper was equal to it, before City hit back in the 29th minute when Elano released Zabaleta - but he saw his effort go high and wide.
A minute later Santander extended their lead with Oscar Serrano starting and finishing the move in superb style.
He found Pereira with a glorious 30-yard ball then took the return in his stride to send a shot beyond Schmeichel.
Santander were cutting City open with ease and Tchite tested Schmeichel with a volley in the 36th minute, following a cross from Pedro Munitis.
There was a brief flare-up 13 minutes later which saw Elano and Cesar Nava both booked by Belgian referee Serge Gumienny.
Santander made it 3-0 in the 55th minute after City failed to cut out a cross from Pedro Munitis.
Marcano headed it on and Juan Valera took full advantage to score from close range.
Schmeichel railed at his defenders and this was becoming embarrassing for City.
Hughes obviously saw the need for damage limitation and brought on Vincent Kompany for the ineffective Elano in the 61st minute.
Santander should have made it 4-0 in the 63rd minute when the referee allowed play to continue after Schmeichel barged into Tchite.
However, faced with an open goal he somehow managed to screw his effort across the face of the area and past the post.
City were anxiously trying to get back in the game but Santander were well-organised at the back.
However substitute Felipe Caicedo pulled a goal back for City in stoppage time when he headed in a cross from Zabaleta - the Ecuadorian's first goal for the club.